September 20, 2013

Additive Found In Dog Food May Prevent A Disabling Chemotherapy Side Effect

A chemical commonly used as a dog food preservative might prevent the kind of painful nerve damage found in the hands and feet of four out of five cancer patients taking the chemotherapy drug Taxol.

A team of Johns Hopkins researchers have been working with cells in test tubes and mice to investigate the Food and Drug Administration (FDA)-approved dog food preservative. The preservative, an antioxidant called ethoxyquin, has been shown to bind certain cell proteins in such a way that their exposure to the damaging effects of Taxol is limited.

The researchers hope that their findings, published online in the Annals of Neurology, will help to build on the protective effects of ethoxyquin's chemistry.

Scientists could possibly develop a drug that could be given to cancer patients before taking Taxol, in much the same way that anti-nausea medication is given to stave off the nausea that commonly accompanies chemotherapy. Currently, approximately half of Taxol users recover from the pain damage, known as peripheral neuropathy. The other half often continue to have debilitating pain, numbness and tingling for the rest of their lives.

"Millions of people with breast cancer, ovarian cancer and other solid tumors get Taxol to treat their cancer and 80 percent of them will get peripheral neuropathy as a result," says Ahmet Höke, MD, PhD, a professor of neurology and neuroscience at the Johns Hopkins University School of Medicine and director of the Neuromuscular Division. "They're living longer thanks to the chemotherapy, but they are often miserable. Our goal is to prevent them from getting neuropathy in the first place."

Prior studies have shown that adding Taxol to a nerve cell line growing in a petri dish would cause neurodegeneration. Höke and his team added Taxol and some 2,000 chemicals -- one at a time -- to see which, if any, might interrupt the degenerative process.

Ethoxyquin did exactly that by making the nerve cells resistant to the toxic effects of Taxol.

Once ethoxyquin's effects were identified in the laboratory grown cell lines, the research team gave Taxol to mice intravenously. They observed nerves in the mice's paws degenerate in only a couple of weeks. When they gave the mice ethoxyquin at the same time as the Taxol, however, it prevented two-thirds of the nerve degeneration. According to Höke, this would have a big impact on quality of life if the same effects were to occur in humans.

Molecules of ethoxyquin bind to Hsp90, which is one of the "heat shock" proteins that cells defensively make more of whenever they are stressed. Basically, Hsp90 is the cell's quality control officer. It determines whether a protein is properly formed before sending it out where it is needed. The team discovered that when ethoxyquin binds to Hsp90, two other proteins — ataxin-2 and Sf3b2 — can't. This forces the cell to see these two proteins as flawed, so they are degraded and their levels in the cell diminished.

So far, the team is unsure why an excess of these two proteins cause a negative effect on nerves, but it is clear that reducing their levels appears in their studies to make cells more resistant to Taxol toxicity.

The team is continuing their investigation into whether this medication might also make nerves more resistant to damage in peripheral neuropathy caused by HIV and diabetes, two other major causes of the pain.

According to Höke, a prior study revealed that ataxin-2 may cause degeneration in motor neurons in a rare form of ALS, commonly known as Lou Gehrig's disease, suggesting that ethoxyquin or some version of it might also benefit people with this disorder.

Peripheral neuropathy affects between 20 and 30 million Americans, making it a "huge public health issue." Höke says that it doesn't receive much attention because it is not fatal.

The team would like to continue their research by conducting safety studies with ethoxyquin in animals in advance of possible testing in people. While too much ethoxyquin is thought to be potentially harmful to dogs, Höke says the needed dose for humans would likely be 20-to-30-fold lower than what is found in dog food.

Ethoxyquin was originally developed in the 1950s as an antioxidant to prevent pears and other foods from discoloring and spoiling.